Treatment of connective tissue diseases of the skin

ABSTRACT

The present invention provides effective and safe medicaments for the treatment of connective tissue diseases of the skin, particularly with respect to the treatment of cutaneous forms of Lupus Erythematous. The medicaments comprise as the therapeutically active ingredient a beta 2  adrenoceptor agonist. The invention furthermore relates to dermatological compositions without skin sensitization properties and which contain enantiomerically pure or enriched R-enantiomers of a beta 2  adrenoceptor agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/867,796, filed Apr. 22, 2013, which is a divisional of U.S.application Ser. No. 11/402,255, filed Apr. 12, 2006, now issued as U.S.Pat. No. 8,426,475, which claims the benefit of Denmark Application PA2005-00529, filed Apr. 13, 2005, all of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the field of pharmacological science.There is provided novel principles of treating connective tissuediseases of the skin, particularly cutaneous manifestations of LupusErythematosus in an individual by administering a beta₂-adrenoceptoragonist to the affected skin areas of the individual. Furthermore, theinvention is directed to topically administrable compositions comprisinga beta₂-adrenoceptor agonist in enantiomeric enriched or pure form.

BACKGROUND OF THE INVENTION

There is no permanent cure for connective diseases of the skin, such ascutaneous forms of Lupus Erythematosus. Today, the treatment ofconnective diseases includes topical treatment with strong steroids,sometimes in combination with anti-malarial drugs or systemicimmuno-suppressants. Unfortunately, the treatment with such drug agentshas serious side effects and cannot be applied for prolonged periods.

The present inventor has recognised the strong need for therapeuticagents that can effectively alleviate the symptoms of cutaneous forms ofLupus Erythematosus (LE) without exhibiting significant adverse effects.Quite surprising, the present inventor has found that the topicalapplication of a beta₂-adrenoceptor agonist effectively relieves theclinical manifestations in cutaneous forms of Lupus Erythematosus.

Cutaneous forms of Lupus Erythematosus (Cutaneous Lupus Erythematosus)encompass at least 10 to 15 different clinical presentations thatusually can be divided into 3 categories, including (1) acute cutaneouslupus erythematosus (ACLE), (2) subacute cutaneous lupus erythematosus(SCLE), and (3) chronic cutaneous lupus erythematosus (CCLE). Some ofthe common types of cutaneous LE include chronic cutaneous lupuserythematosus (CCLE) and various sub-types thereof.

Current evidence indicates that cutaneous Lupus Erythematosus is aseparate disease from systemic Lupus Erythematosus and not just a benignvariant of systemic LE in that the two diseases seems to be geneticallydifferent diseases (Rook's, Textbook of Dermatology, chapter 65, page56.2, volume 3, 7^(th) edition, edited by Tony Burns et al, BlackwellScience, 2004). Systemic Lupus Erythematosus (SLE) is the most commonconnective tissue disease and is characterised by multi-organinflammation, which most commonly affects the skin, joints andvasculature. Almost any organ or system of the body, including thelungs, kidneys, heart or brain may be affected by the inflammation.

Beta₂-adreneroceptor agonists are traditionally used in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and nervoussystem injury. Beta₂-adrenoceptor agonists has also been found tointeract with specific receptors on T-lymphocytes to mediateanti-inflammatory activities (Baramki D et al. Modulation of T-cellfunction by (R)- and (S)-isomers of albuterol: anti-InflammatoryInfluences of (R)-isomers are negated in the presence of the (S)-isomer.J Allergy Clin Immunol 2002 March; 109(3):449-54) and Barnes P J. Effectof beta-agonists on inflammatory cells. J Allergy Clin Immunol 1999August; 104(2 Pt 2):S10-S1)7.

A number of drug agents and combinations thereof have been proposed forthe treatment of various inflammatory diseases including discoid LupusErythematosus, wherein a beta₂-adrenoceptor agonist among other drugagents is proposed to be administered as a secondary active drug agent.

The patent application US2005192261 relates to topical treatment withcombinations of an antihistamine or an antihistamine analogue and acorticosteroid.

The patent application WO05051293 relates to topical treatment withIbudilast or a related compound.

The patent application US2004220153 relates to topical treatment with aselective serotonin reuptake inhibitors (SSRI).

The patent application US2004224876 relates to topical treatment with anon-steroidal immunophilin-dependent immunosuppressant (NsIDI) and anNsIDI enhancer (NsIDIE).

Notably, none of the above-mentioned patent application relates to thedirect treatment of cutaneous forms of LE with a beta₂-adrenoceptoragonist, neither as the sole therapeutically agent nor as the primarytherapeutically agent.

Furthermore, a number of treatment regimens have been proposed for thetreatment of systemic LE. In these treatments, the primarytherapeutically effective drug agent eventually may be co-administeredwith a beta₂-adrenoceptor agonist:

The patent application WO2003092617 relates to the treatment of aninflammatory skin disease, such as systemic Lupus Erythematosus, bytopically administering a steroid and a beta-adrenergic receptor ligand.

The patent application US2003236298A1 (Atherogenics Pharmaceuticals,Inc) relates to 1,3-bis-(substituted-phenyl)-2-propen-1-ones that areinhibitors of the expression of VCAM-1 for the treatment of patientswith a disease mediated by VCAM-1, such as systemic Lupus Erythematosus.

The patent applications US2005130935 and WO 2003097073 (AstionDevelopment A/S) relate to combinations of a beta₂-adrenoceptor agonistand an aminosugar for the treatment of inflammatory diseases, includingsystemic Lupus Erythematosus.

The patent applications US20050176714 and WO2003104204 relate topyridazine derivatives acting as phosphodiesterase IV inhibitors for thetreatment of autoimmune diseases, such as systemic Lupus Erythematosus.

Furthermore, unusual respiratory manifestations of systemic LupusErythematosus, “shrinking lungs” have been treated with albuterol(Salbutamol) (Thompson P J, Dhillon D P, Ledingham J, Turner-Warwick M.Shrinking lungs, diaphragmatic dysfunction, and systemic LupusErythematosus. Am Rev Respir Dis. 132(4), 926-8, 1985).

Topical administration of beta₂-adrenoceptor agonists has been shown toresult in sensitization of the skin and allergic reactions. For example,salbutamol (albuterol) has been reported to be a topical sensitizer thatcauses contact dermatitis reactions when applied to the surface of theskin of humans (in Biochemical Modulation of Skin Reactions, page 10-11,edited by Agis K. Kydonieus and John J. Wille, CRC Press LCC 2000).

However, the present inventor has overcome this problem by providingtopically administrable compositions only or mainly comprising theR-enantiomeric form of a beta₂-adrenoceptor agonist.

Topically administrable compositions comprising an enantiomerically purebeta₂-adrenoceptor agonist have been disclosed in the art:

The patent application US2005192261 discloses topical compositionsprimarily comprising an antihistamine or an antihistamine analogue and acorticosteroid.

The patent application WO05051293 (COMBINATORX, INCORPORATED) disclosestopical compositions primarily comprising Ibudilast or relatedcompounds.

The patent application US2004220153 discloses topical compositionsprimarily comprising selective serotonin reuptake inhibitors (SSRI).

The patent application US2004224876 discloses topical compositionsprimarily comprising a non-steroidal immunophilin-dependentimmunosuppressant (NsIDI) and an NsIDI enhancer (NsIDIE).

The patent application WO2003092617 (COMBINATORX, INCORPORATED)discloses topical compositions comprising a steroid and abeta-adrenergic receptor ligand.

Topical compositions of a beta₂-adrenoceptor agonist are proposed inseveral documents, but these fail to emphasise the importance ofadministering the enantiomeric pure form: The patent application U.S.Pat. No. 4,574,129 (Bristol-Myers Company) discloses topicalcompositions comprising a beta₂-adrenoceptor agonist and vehiclematerials for the treatment of topical anti-inflammatory effect inmammals.

The U.S. Pat. No. 4,699,777 (Schering Corporation) discloses transdermalcompositions of albuterol further comprising 5 to 50% of1-dodecyl-azacycloheptan-2-one and 5 to 50% of non-aqueous urea.

The U.S. Pat. No. 4,975,466 (Ciba-Geigy Corporation) discloses topicalcompositions based on Formoterol and related compounds for use in thetreatment of inflammatory skin diseases.

The U.S. Pat. No. 4,980,159 (Bristol-Myers Squibb Company) disclosespost-shave compositions (aqueous solutions) comprising abeta₂-adrenoceptor agonist for pilomotor effects.

The U.S. Pat. No. 6,267,972 (Societe L'Oreal S.A) disclosescosmetic/pharmaceutical compositions for the treatment of cutaneousdiseases and sensitive skin comprising an effective substance Pantagonist amount of at least one beta₂-adrenoceptor agonist togetherwith an skin irritant.

The patent application WO05102296 (HEPTAGEN LIMITED) discloses topicalcompositions comprising a combination of vitamin D or an analogue,preform or derivative thereof, a cannabinoid or cannabinoid receptoragonist, and a beta₂-adrenoceptor agonist for the treatment ofpsoriasis.

The patent application WO03088997 (UNIVERSITEIT UTRECHT HOLDING B.V)discloses topical compositions of an antigen and a beta₂-adrenoceptoragonist for the induction of tolerance to treat autoimmune diseases,delayed type hypersensitivity reactions and/or transplant rejection,and/or graft versus host reaction and/or allergic reactions.

The patent application US2003236298A1 (Atherogenics Pharmaceuticals,Inc) discloses topical compositions of1,3-bis-(substituted-phenyl)-2-propen-1-ones inhibiting the expressionof VCAM-1.

The patent application US2005130935A1 (Astion Development A/S) disclosescombinations of beta₂-adrenoceptor agonist and an aminosugar for thetreatment of inflammatory diseases.

The patent application JP7304647 (KAO CORP) discloses compositions formassage comprising one or more compounds selected from (A): (i) axanthine derivative, (ii) a beta-adrenergic agent, (iii) an alpha-2adrenergic activity inhibitor, and (iv) a bipyridine derivative; and (B)a scrubbing agent.

The patent application JP9110674 (KAO CORP) discloses a bathingcomposition comprising a compound of the plant of pepper family (e.g.Piper nigrum L, Piper longum L, Piper angustifolium), carbonate and anorganic acid.

The patent application JP 61-154201(TEIJIN LTD) discloses transdermalcompositions comprising a β-stimulation agent and a dissolutionassistant agent.

The patent application JP 06-048497 (Kao Corp) discloses a bathing agentcomposition containing a β-adrenergic stimulant, inorganic salt, anorganic acid and an oily component.

The patent application U.S. Pat. No. 4,088,756 (The Regents of theUniversity of Michigan) relates to topically applied compositionscomprising at least one active compound selected from the groups α1, β1,and β2-adrenergic agents and oral hypoglycemic agents.

The patent application WO05102296A2 (HEPTAGEN LIMITED) relates totopically applied compositions comprising vitamin D or its analogue,cannabinoid or a cannabinoid receptor agonist; and a beta-adrenoceptoragonist for the treatment of immuno-proliferative skin diseases.

The patent application WO2003092617 (COMBINATORX, INCORPORATED) relatesto topically applied compositions comprising a steroid and abeta-adrenergic receptor agonist for the treatment of an inflammatoryskin disease.

The patent application WO9519336 (IOVIS BIOMEDICAL AND PHARMACEUTICALCONSULTANTS) relates to phenyl ethanol amine ethers acting as betaadrenergic agonists that may be applied topically to skin.

Notably, none of the above-mentioned patents and patent applicationsdisclose topically administrable compositions, wherein thebeta₂-adrenoceptor agonist is the primary therapeutical agent or thesole therapeutical agent.

SUMMARY OF THE INVENTION

Surprisingly, the present inventor has found that beta₂-adrenoceptoragonists (in short “beta₂ agonist”) have strong therapeutic potential inthe treatment of cutaneous forms of Lupus Erythematosus, even whenapplied as the sole therapeutically active ingredient to a patient withcutaneous LE. Clinical data shown herein clearly demonstrate thesignificant improvement of inflamed lesions after only 3 weeks treatmentwith topical Salbutamol to a patient suffering from Discoid LupusErythematosus. In another patient diagnosed with Sub-acute CutaneousLupus Erythematosus, complete remission of the cutaneous symptoms wasobserved after 8 weeks of treatment with topical Salbutamol. Notably,these patients have had the diseases for several years, where treatmentwith strong corticosteroids had only little effect.

Therefore, the present invention provides significant improvements inthe treatment of cutaneous forms of LE even in patients that are notresponding well to gluco-corticosteroids.

The clinical data are very surprising since cutaneous LupusErythematosus are very difficult to treat.

Contrarily to existing therapeutic agents applied in the treatment ofcutaneous Lupus Erythematosus, the beta₂-adrenoceptor agonists accordingto the present invention have the advantage of not being likely to beassociated with any serious side effects, as these agonists are safe andwell tolerated by the organism in pharmacologically relevant doses.Cutaneous forms of Lupus erythematosus are characterised by patchydermal lymphocytic infiltrates, where the majority of infiltratinglymphocytes are T-lymphocytes expressing antigens. Without being limitedto a particular theory, the present findings of the novel use ofbeta₂-adrenoceptor agonists can be extended to all skin diseases wherethe pathology, at least in part, involves expression of beta₂ receptorsin leukocytes, such as in the T-lymphocyte. Typically, such skindiseases presenting dermal lymphocytic infiltrates include all kinds ofconnective tissue diseases.

Therefore, the present invention relates in a first aspect to a methodfor the treatment or prevention of cutaneous Lupus Erythematosus oranother connective tissue disease affecting the skin in an individual.The method comprises administration to said individual of an effectiveamount of a therapeutically active ingredient in the form of abeta₂-adrenoceptor agonists, a stereoisomer thereof, an enantiomerthereof, a physiologically acceptable derivative thereof, and/or apharmaceutically acceptable salt thereof. Preferably, the treatment iseffected by mono-therapy, wherein no other therapeutically effectiveingredient is administered together with the beta₂-adrenoceptoragonists. Furthermore, the administration is preferably effected bytopical application to skin.

The inventor has furthermore solved the problem with topicalsensitization of skin caused by beta₂-adrenoceptor agonists by selectingthe particular enantiomer that is pharmacologically active and whichdoes not cause sensitization reactions in skin.

Therefore, a second aspect of the invention relates to a topicallyadministrable pharmaceutical composition comprising:

i) a therapeutically active ingredient in the form of enantiomericallyenriched or enantiomerically pure R-enantiomer of a beta₂-adrenoceptoragonist, a physiologically acceptable derivative thereof or apharmaceutically acceptable salt thereof; and

ii) one or more dermatologically acceptable excipients or carriers.

The therapeutically active ingredient is preferably the soletherapeutically agent, or at least the primary therapeutically activeingredient included in the topically administrable composition.

Where it is desirable to employ additionally therapeutically activeingredients in the methods, medicaments and topically administrablecompositions of the invention, the following therapeutically activeingredients are considered as less relevant or suitable for thetreatment of connective tissue diseases of the skin and are ratherexcluded from such methods, medicaments and compositions. Such atherapeutically active ingredient may be selected from a steroid;Ibudilast or a related compound; a selective serotonin reuptakeinhibitor (SSRI); a non-steroidal immunophilin-dependentimmunosuppressant (NsIDI), an anti-histamine; or an aminosugar).

Topically administrable compositions of this invention have thesignificant advantage of being devoid of cutaneous atrophy associatedwith treatment with topical gluco-corticosteroids, which have so farbeen the mainstay treatment of cutaneous Lupus Erythematosus.

DETAILED DESCRIPTION OF THE INVENTION

The present inventor has recognised the beneficial effect of a beta₂agonist in treating connective tissue diseases, particularly in thetreatment of cutaneous forms of Lupus Erythematosus.

Accordingly, a first aspect of this invention relates to a method forthe treatment or prevention of a connective tissue disease of the skin,such as cutaneous forms of Lupus Erythematosus. The method comprisesadministration of a sufficient amount of a beta₂ agonist, a stereoisomerthereof, an enantiomer thereof, a physiologically acceptable derivativethereof, and/or a pharmaceutically acceptable salt thereof to theaffected skin areas of an individual in need thereof. More particularly,the beta₂ agonist may in some embodiments be the sole therapeuticallyactive ingredient to be administered or at least be the primary/firsttherapeutically active ingredient to be administered.

Thus, the invention is meant to be directed to the prevention,alleviation and treatment of cutaneous manifestations in an individualsuffering from or diagnosed with a connective tissue disease of theskin, such as cutaneous forms of Lupus Erythematosus.

As used herein, the phrase “cutaneous forms of Lupus Erythematosus” and“cutaneous Lupus Erythematosus” are meant to be interchangeable phrasesencompassing various types of LE that have cutaneous manifestations ofthe disease in the skin or mucosa of an individual. Such cutaneous formsof LE are typically characterised by the presence of the immunoglobulinsIgG, IgA and IgM and complements at the dermal-epidermal junction inskin lesions for 6 weeks or more (Rook's, Textbook of Dermatology,chapter 65, pages 56.5 to 56.69, volume 3, 7^(th) edition, edited byTony Burns et al, Blackwell Science, 2004). Some experts tend tocategorise cutaneous forms of LE into three major types; (1) AcuteCutaneous Lupus Erythematosus (ACLE), (2) Subacute Cutaneous LupusErythematosus (SCLE), and (3) Chronic Cutaneous Lupus Erythematosus(CCLE). A major form of CCLE is Discoid Lupus Erythematosus (DLE) existstogether with many sub-groups of cutaneous LE, such as hypertrophic LE(a form of DLE), Verrucous LE (a form of DLE), Tumid LE, lupuspanniculitis, disseminated DLE, Bullous SLE, Telangietactic LE,Chilblain lupus, Childhood DLE, Lupus Erythematosus Profundus andMucosal DLE. The phrase “cutaneous forms of Lupus Erythematosus” is alsomeant to encompass cutaneous manifestations of systemic LE. For examplein connection with treating cutaneous manifestations in a subjectdiagnosed with SLE.

Therefore, in interesting embodiments of the present invention thetreatment of cutaneous forms of Lupus Erythematosus includes thetreatment of Acute Cutaneous Lupus Erythematosus, Subacute CutaneousLupus Erythematosus, Chronic Cutaneous Lupus Erythematosus, cutaneousmanifestations of Systemic Lupus Erythematosus, and various sub-groupsthereof, such as Discoid Lupus Erythematosus, Hypertrophic LupusErythematosus, Verrucous Lupus Erythematosus, Tumid Lupus Erythematosus,Lupus Panniculitis, Disseminated Discoid Lupus Erythematosus, BullousSystemic Lupus Erythematosus, Telangietactic Lupus Erythematosus,Chilblain lupus, Childhood Discoid Lupus Erythematosus, LupusErythematosus Profundus and/or Mucosal Discoid Lupus Erythematosus.

The terms “cutaneous manifestations” and “cutaneous presentations” areinterchangeable terms, which refer to a pathological or clinical featurepresent in the skin or in the mucosa of an individual in risk of,suffering from, or diagnosed with a connective tissue disease of theskin.

Typical cutaneous manifestations (either pathologically or clinically)of cutaneous forms of Lupus Erythematosus include the presence of apatchy dermal lymphocytic infiltrates; liquefaction degeneration of thebasal cell layer of the epidermis; oedema of the connective tissue belowthe epidermis; fibrinoid of the connective tissue below the epidermis;atrophy of the dermis; keratotic plugging: thinning and pallor of theepidermis with relative hyperkeratosis and plugging of the follicularmouth; thickening of the basement membrane of the epidermis andsometimes small vessels; premature elastotic degeneration of collagen inlight exposed areas.

A typical clinical feature is skin rash, chilblain-like lesions,alopecia in scalp lesions, well-defined erythematous patches which maycontain scales, hyperkeratosis, telangiectasia, nodular lesions,non-scarring papulosquamous lesions and annular polycyclic lesions.

The cutaneous manifestations may be limited to the skin, such as theskin of scalp, ears, nose, lips, arms, legs, fingers, feet, toes,breast, and trunk. Furthermore, the cutaneous manifestations may befound in the buccal mucosa, such as lips and tongue and in the mucosa ofvulva and anus.

The term “DLE” defines a connective-tissue disease affecting only theskin, most frequently the skin in the face, neck and the scalp. DLE ischaracterised by well-defined red scaly patches of variable size(coin-shaped red bumps), which heal with atrophy, scarring andpigmentary changes. As DLE lesions heal, they leave thickened, scarredareas of skin. When the scalp is severely affected, there may beassociated hair loss (alopecia). DLE is sometimes called chroniccutaneous lupus erythematosus (CCLE).

The term “SCLE” defines a specific subset of lupus and may becharacterised as a non-scarring non-atrophy-producing photosensitivedermatosis. SCLE may occur in patients with systemic Lupus Erythematosus(SLE), Sjögren syndrome, and in patients with deficiency of the secondcomponent of complement (C2d). It may also be drug induced. Somepatients also have the lesions of DLE, and some may develop small vesselvasculitis. Therefore, SCLE may be regarded as a cutaneous diseasecategorised as an intermediate between discoid Lupus Erythematosus andsystemic Lupus Erythematosus. SCLE may accompany other diseases or thetreatment of such diseases, such as in the course of PUVA treatment ofpsoriasis, radiation therapy, or in connection with cancer, such as forexample Hodgkin's disease, cancers of the lung, breast and liver.

The term “ACLE” defines a “butterfly rash”. The butterfly rash has anabrupt onset and can last for hours or days, and usually heals withoutscarring. Typically, it is localized in the face, but it could occuranywhere on the body. Typically, it is present in patients diagnosedwith SLE. Variations of this rash have been observed, including bullousformations or blisters.

Systemic Lupus Erythematosus (SLE) is regarded as a distinct diseasefrom the cutaneous forms of Lupus Erythematosus. Individuals diagnosedwith SLE may have cutaneous manifestations, such as cutaneousmanifestations typically found in ACLE, SCLE and DLE. Some individualsmay suffer from Bullous systemic lupus erythematosus that showscutaneous manifestations.

Therefore, the phrase “cutaneous manifestations of systemic LupusErythematosus” is meant to encompass that some patients diagnosed withSystemic Lupus Erythematosus also have cutaneous disease, such ascutaneous manifestations similar to those found in patients diagnosedwith ACLE, SCLE and DLE.

As mentioned, the underlying pharmacodynamic principle of this inventionrelates to enhancing the activity of beta₂ adrenergic receptors in theskin, where such beta₂ adrenergic receptors at least are expressed inleukocytes, such as in the T-lymphocyte and wherein the agonisticactivity of a beta₂ agonist reduces the skin lesions.

Therefore, a beta₂ agonist may be used in the treatment of all kinds ofskin diseases where the lymphocytic infiltration in the epidermis,dermis, and/or mucosa is a pathological feature of the skin disease.

Therefore, according to this invention another connective tissue diseaseof the skin may be treated with a beta₂ agonist. The term “connectivetissue diseases” refer to a heterogeneous group of diseases, somehereditary, others acquired, characterized by abnormal structure orfunction of one or more of the elements of connective tissue, i.e.,collagen, elastin, or the mucopolysaccharides and wherein the skin canbe affected. The phrase, “connective tissue diseases of the skin” ismeant to define a connective tissue disease that has cutaneousmanifestations. Thus, the connective tissue disease may be a systemicdisease where the skin is affected or a cutaneous disease mainly or onlyaffecting the skin. Examples of connective tissue diseases of the skininclude at least Scleroderma, Morphoea, Pseudoscleroderma, Occupationalscleroderma, Graft-versus-host disease, Eosinophilic fasciitis,Connective tissue panniculitis, Systemic Sclerosis; Mixed connectivetissue disease; Lichen sclerosus; Sclerederma; Dermatomyositis;Rheumatoid disease; Still's disease; Sjögrens syndrome and Rheumaticfever.

Still other related diseases where lymphocytic infiltrations are apathological feature of the skin disease are Jessner's lymphocyticinfiltration, polymorphic light eruption (PLE), lymphocytic lymphoma,lymphocytoma cutis and Pemphigous erythematosus.

The term “an individual in need thereof” is meant to define a human oran animal, such as a mammal that is in need of treatment of a connectivetissue disease of the skin. The term “an individual” refers to ananimal, and yet more typically a mammal. The term “Mammal” as usedherein refers to any animal classified as a mammal, including humans,domestic and farm animals, zoo, sports, or pet animals, such as dogs,horses, cats, cattle, etc. Preferably, the individual is a human, a cat,a dog or a horse.

According to the invention, any cutaneous form of LE or other connectivetissue diseases of the skin that affects both humans and animals can betreated with a beta₂ agonist. For example, the treatment, uses andmedicaments described herein may be applied in the treatment of Lupoiddermatitis in the dog and Hyperelastosis cutis in the horse.

Beta₂-Adrenoceptor Agonist (Beta₂ Agonist)

According to the underlying principle of the present invention, any drugagent or pharmacological tool exhibiting the above-mentioned beta₂agonistic-activities may be applied in compositions, methods and uses asdefined herein.

The term “beta₂-adrenoceptor agonist” or “beta₂ agonist” is intended tomean any drug agent or pharmacological tool of inorganic, organic andbiological nature with the ability to selectively or partiallystimulate/activate beta₂-adrenergic receptors. These receptors areG-protein coupled receptors widely distributed in animals and humans andactivated by endogenous catecholamines, and which play important rolesin regulating cardiac, vascular, pulmonary, and metabolic functions.

The beta₂ agonist is preferably an organic molecule.

In one embodiment of the invention, the beta₂ agonist of the inventionis a selective binding partner or at least a predominant binding partnerfor a beta₂-adrenergic receptor.

In another embodiment of the invention, the beta₂ agonist of theinvention may also exert binding capacity to other families ofreceptors, such as α1, α2 β1 and β3-adrenergic receptors, as long as theagonistic activity towards β₂-adrenergic receptors is sufficient toobtain the desired effects according to the invention. Thus, the beta₂agonist may exhibit unspecific binding to a beta₂-adrenergic receptor.

The beta₂-agonistic activity of a drug agent or pharmacological tooltowards beta₂-adrenergic receptors is easily confirmed by methods knownto the person skilled in the art. One example is by testing theagonistic activity in a binding assay using a ligand representing thebeta₂-adrenergic receptors, such as the binding assay conducted by MDSPharma Services (Catalogue no. 204110 MDS Pharma Services Discovery,2004-2005). The agonistic activity is determined by the measure of theconcentration (nM) of the beta₂ agonist required to produce half maximaleffect (EC₅₀). The concentration required should in general be less than10.000 nM as measured by the binding-based assay conducted by MDS PharmaServices or according to a similar binding-based assay. Theconcentration resulting in EC₅₀ is preferably less than 7000 nM, morepreferably less than 5000 nm, such as less than 4000, 3000, 2000, 1000,800, 700, 600, 500, 400, 300, 250, 200, 150, 100, 80, 60, 40, 20 or 10nM.

According to another alternative, the agonist activity of the beta₂agonist of the invention may be determined by a cell assay described byMcCrea and Hill S J. (McCrea and Hill S J. Salmeterol, a long-actingbeta ₂-adrenoceptor agonist mediating cyclic AMP accumulation in aneuronal cell line. Br J Pharmacol. 1993; 110:619-26.) In one embodimentof the invention, the beta₂ agonist of the invention has a relativepotency to a selective agonist, such as formoterol or terbutaline,between 0.01 and 1000, preferably between 0.1 and 500, such as between 1and 200 when tested in the above-mentioned cell assay of McCrea and HillS J.

According to still another alternative, the beta₂ agonist of theinvention has a relative potency to salbutamol of at least 0.01 and upto 1000 with respect to acting as a beta₂ agonist in the above-mentionedbinding-based assay or cell assay. Preferably, the beta₂ agonist has arelative potency to salbutamol ranging between 0.02 and 500, morepreferably between 0.1 and 100 when tested in the above-mentioned cellassay of McCrea and Hill S J.

Currently, a number of beta₂ agonists are available. Most of them have astructure related to catecholamines. Therefore, in one embodiment of theinvention the beta₂ agonist is selected from the group of beta₂ agoniststhat comprises, as part of their backbone structure, the followingstructural formula I:

The terms, Z, Y and X, are meant to define substituents of the phenylrings of structural formula I so as to define un-substituted,mono-substituted, di-substituted or tri-substituted phenyl ring, whereinZ, Y and X may be the same or different.

According to the invention, the terms Z, X, and Y may independentlydesignate radicals selected from hydrido (H), optionally substitutedC₁₋₆-alkyl, C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxyl,phenyl, C₇₋₁₄ alkaryl, C₇₋₁₄ alkheterocyclyl, acyl (OOR′), cyano (CN),urea (NH—CO—NH2), formamide (NH—CO), trihalogenmethyl, halogen (Br, Cl,F, I), hydroxy (OH), hydroxy derivative (OR′), primary amino (NH₂),secondary amino (NHR′), tertiary amino (NR′R″), carboxy (CO), carboxyderivative (CO—R′), sulfonyl (HSO₂), sulfonyl derivative (R′—SO_(2′))and sulfonamide (NH—SO₂—R′). Furthermore, two of the groups selectedfrom Z, X and Y may together form a 5 or 6 membered carbon ring or acarbon ring with one nitrogen atom (N) in the ring, e.g. where Z and X,Y and X, or Y and Z together forms a 5 or 6 membered carbon ring or acarbon ring with one nitrogen atom in the ring (a hetero ring).

The terms “R₁” and “R₂” refer to substituents of the amino atom that areattached to carbon atom 2 (C₂) of structural formula I. R₁ and R₂ mayindependently designate a radical selected from hydrido (H), C₁₋₆-alkyl,C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxyl, C₇₋₁₄alkaryl, C₇₋₁₄ alkheterocyclyl, and R₁ and R₂ may together form a 5 or 6membered carbon ring or a carbon ring with one nitrogen atom (N) in thering.

The term “R₃” represents a radical selected from hydrido (H), halogen(Br, Cl, FI, I), C₁₋₆-alkyl, C₄₋₆-cycloalkyl, C₂₋₆-alkenyl andC₂₋₆-alkynyl.

The terms R′ and R″ independently define a radical selected fromC₁₋₆-alkyl, C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxyl,C₇₋₁₄ alkaryl, C₇₋₁₄ alkheterocyclyl, preferably C₁₋₆-alkyl,C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₂₋₆-alkoxyl.

The term “C₁₋₆-alkyl” is meant to define saturated, straight-chained orbranched alkyl radical containing from 1 to 6 carbon atoms, e.g. allalkyl radicals from methyl up to hexyl including all isomers thereof,e.g. iso-butenyl.

The term “C₂₋₆-alkenyl” defines unsaturated straight chained or branchedalkylene radicals containing from 2 to 6 carbon atoms, e.g. 1- or2-propenyl, 1-, 2- or 3-butenyl and the like and isomers thereof.

“C₂₋₆-alkynyl” defines unsaturated chained or branched alkynyl radicalscontaining from 2 to 6 carbon atoms, e.g. ethynyl, 1- or 1-propynyl, 1-,2- or 3-butynyl and the like and isomers thereof.

The term “C₁₋₆-alkoxyl” means alkoxy radicals containing up to 6 andpreferably up to 4 carbon atoms, e.g. methoxy, ethoxy, propoxy etc.

The term “C₄₋₇-cycloalkyl” means a cycloalkane having from 4 to 7 carbonatoms, such as cyclobutane, cyclopentane and cyclohexane.

The term “C₇₋₁₄ alkaryl” embraces aryl-substituted alkyl radicals suchas benzyl, diphenylmethyl, phenethyl, and diphenethyl having from 7 to14 carbon atoms.

The term “C₇₋₁₄ alkheterocyclyl” designates an alkyl substitutedheterocyclic group having from 7 to 14 carbon atoms in addition to oneor more heteroatoms, N, S, P, or O (e.g. 3-furanylmethyl,2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2tetrahydrofuranylmethyl) Nonlimiting examples of heterocylics arepyrrolidinyl, tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl,tetrahydropyranyl, piperazinyl, piperidinyl, morpholino, thiomorpholino,tetrahydropyranyl, imidazolyl, pyrrolinyl, pyrazolinyl, indolinyl,dioxolanyl, or 1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl,pyridinyl, pyridazinyl, pyrimidinyl.

The groups, C₁₋₆-alkyl, C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-alkoxyl, C₇₋₁₄ alkaryl, and C₇₋₁₄ alkheterocyclyl may optionally bemono or di-substituted with primary amino (NH₂), secondary amino (NHR′),tertiary amino (NR′R″), OH, cyano, nitro and halogen, wherein R′ and R″are as defined herein.

The term “halogen” defines bromine, chlorine, fluorine and iodine.

The term “hydrido” designates a single hydrogen atom (H).

In one embodiment, the terms Z, X, and Y may independently designateradicals selected from hydrido (H), optionally substituted C₁₋₆-alkyl,C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxyl, phenyl, C₇₋₁₄alkaryl, C₇₋₁₄ alkheterocyclyl, (OOR′), cyano (CN), urea (NH—CO—NH2),formamide (NH—CO), trihalogenmethyl, halogen (Br, Cl, F, I), hydroxy(OH), hydroxy derivative (OR′), primary amino (NH₂), secondary amino(NHR′), tertiary amino (NR′R″), carboxy (CO), carboxy derivative(CO—R′), sulfonyl (HSO₂), sulfonyl derivative (R′—SO_(2′)) andsulfonamide (NH—SO₂—R′), wherein R′ and R″ preferably designatesC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₁₋₆-alkoxyl.

In one further preferred embodiment, the phenyl ring of structuralformula I defines un-substituted, mono-substituted or di-substitutedphenyl ring, wherein Z and Y may be the same or different and X ishydrido (H).

Furthermore, in still further embodiments, the groups, C₁₋₆-alkyl,C₄₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxyl, C₇₋₁₄alkaryl, and C₇₋₁₄ alkheterocyclyl may optionally be mono-substitutedwith primary amino (NH₂), secondary amino (NHR′), OH, cyano, nitro andhalogen, wherein R′ and R″ are as defined herein, such as preferablywherein R′ and R″ preferably designates C₁₋₆-alkyl, C₄₋₆-cycloalkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₁₋₆-alkoxyl.

The compounds of the present invention may contain one or moreasymmetric carbon atom. Therefore, the instant invention may alsoinclude the individual diastereomers and enantiomers, which may beprepared or isolated by methods known to those skilled in the art. Forexample, the carbon atom designated C₁ represents an asymmetric carbonatom and compounds of structural formula I may be provided as a racemateor as enantiomerically pure or enantiomerically enriched “R” or “S”forms.

Examples of beta₂ agonists with a backbone structure according tostructural formula I are:

-   Amiterol (4-Amino-[[(1-methylpropyl)amino]methyl]benzenemethanol);-   Bamethan ((Butylamino)methyl]-4-hydroxybenzenemethanol);-   Bitolterol    (4-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,2-phenylene    4-methylbenzoate);-   Butaxamine    (α-1-[[(1,1-Dimethylethyl)amino]ethyl]-2,5-dimethoxybenzenemethanol);-   Carbuterol    ([5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxyphenyl]urea);-   Clenbuterol    (4-Amino-3,5-dichloro-[[(1,1-Dimethylethyl)amino]methyl]-benzenemethanol);-   Clorprenaline    (2-Chloro-[[(1-methylethyl)amino]methyl]benzenemethanol);-   Colterol    (4-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,2-benzenediol);-   Deterenol (4-Hydroxy-[[(1-methylethyl)amino]methyl]benzenemethanol);-   Dioxethedrin (4-[2-(Ethylamino)-1-hydroxypropyl]-1,2-benzenediol);-   Etafedrine ([1-(Ethylmethylamino)ethyl]benzenemethanol);-   Ethylnorepinephrine (2-Amino-1-(3,4-dihydroxyphenyl)-1-butanol);-   Fenoterol    (5-[1-Hydroxy-2-[[2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-1,3-benzenediol);-   Flerobuterol    (α-[[(1,1-Dimethylethyl)amino]methyl]-2-fluorobenzenemethanol);-   Formoterol    (N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide);-   Hexoprenaline    (4,4′-[1,6-Hexanediylbis[imino(1-hydroxy-2,1-ethanediyl)]]bis-1,2-benzenediol);-   Indacaterol    (5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-2(1H)-quinolinone);-   Isoetarine    (4-[1-Hydroxy-2-[(1-methylethyl)amino]butyl]-1,2-benzenediol);-   Isoproterenol(Isoprenaline,    (4-[1-Hydroxy-2-[(1-methylethyl)amino]ethyl]-1,2-benzenediol);    Mabuterol    (4-Amino-3-chloro-[(dimethylethylamino)methyl]-5-(trifluoromethyl)benzene    methanol);-   Medroxalol    (5-[2-[[3-(1,3-Benzodioxol-5-yl)-1-methylpropyl]amino]hydroxyethyl]-2-hydroxybenzamide);-   Meluadrine    (2-Chloro-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxybenzenemethanol);-   Nardeterol    (α-[[[3-(1H-Benzimidazol-1-yl)-1,1-dimethylpropyl]amino]methyl]-2-fluoro-4-hydroxybenzenemethanol);-   2-(Methylamino)-1-phenyl-1-propanol;-   Norbudrine (4-[2-(Cyclobutylamino)-1-hydroxyethyl]-1,2-benzenediol);-   Norepinephrine    (Arterenol,4-(2-Amino-1-hydroxyethyl)-1,2-benzenediol);-   Orciprenaline (Metaproterenol,    5-[1-Hydroxy-2-[(1-methylethyl)amino]ethyl]-1,3-benzenediol);-   Picumeterol    (4-Amino-3,5-dichloro-[[[6-[2-(2pyridinyl)ethoxy]hexyl]amino]methyl]-benzenemethanol);-   Pirbuterol    (6-[[(1,1-Dimethylethyl)amino]methyl]-3-hydroxy-2,6-pyridinedimethanol);-   Procaterol    (8-Hydroxy-5-[1-hydroxy-2-[(1-methylethyl)amino]butyl]-2(1H)-quinolinone);-   Protokylol    (4-[[2-[2-(1,3-Benzodioxol-5-yl)-1-methylethyl]amino]-1-hydroxyethyl]-1,2-benzenediol);-   Quinprenaline    (8-Hydroxy-[[(1-methylethyl)amino]methyl]-5-quinolinemethanol);-   Reproterol    (7-[3-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]propyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);-   Rimiterol (4-(Hydroxy-2-piperidinylmethyl)-1,2-benzenediol);-   Salbutamol, (Albuterol    (1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol);-   Salmefamol    (4-Hydroxy-′-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]-1,3-benzenedimethanol);-   Salmeterol    (4-Hydroxy-′-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol);-   Soterenol (N-[2-Hydroxy-5-[1-hydroxy-2-[(methylethyl)amino]ethyl]    phenyl]-methanesulfonamide);-   Sulfonterol    (α-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-3-[(methylsulfonyl)methyl]-benzenemethanol);-   Terbutaline    (5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol);-   Tulobuterol    (2-Chloro-[(1,1-dimethylethylamino)methyl]benzenemethanol);-   Zilpaterol    (4,5,6,7-Tetrahydro-7-hydroxy-6-[(1-methylethyl)amino]imidazo[4,5,1-jk][1]benzazepin-2(1H)-one);-   Zinterol    (N-[5-[2-[(1,1-Dimethyl-2-phenylethyl)amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide).

Therefore, some embodiments of the invention include a beta₂ agoniststhat is a catecholamine derivative selected from the group comprisingAmiterol; Bamethan; Bitolterol; Butaxamine; Carbuterol; Cimaterol;Colterol; Clenbuterol; Clorprenaline; Colterol; Deterenol; Dioxethedrin;Etafedrine; Ethylnorepinephrine; Fenoterol; Flerobuterol; Formoterol;Hexoprenaline; Indacaterol; Isoetarine; Isoproterenol(Isoprenaline);Mabuterol; Medroxalol; Meluadrine; Nardeterol; Norbudrine;Norepinephrine (Arterenol); Orciprenaline (Metaproterenol); Picumeterol;Pirbuterol; Procaterol; Protokylol; Quinprenaline; Reproterol;Rimiterol; Salbutamol (Albuterol); Salmefamol; Salmeterol; Soterenol;Sulfonterol; Terbutaline; Tulobuterol; Zilpaterol; Zinterol; astereoisomer thereof; a physiologically acceptable derivative thereof; apharmaceutically acceptable salt thereof; and mixtures thereof.

Further examples of beta₂ agonists include those, which as part of theirbackbone have a structure closely related to the above-mentionedstructural formula I, but where the asymmetric carbon atom (C₁) ismissing:

Un-limited examples are:

-   Broxaterol    (3-Bromo-[[(1,1-dimethylethyl)amino]methyl]-5-isoxazolemethanol)-   Methoxyphenamine (2-Methoxy-N,-dimethylbenzeneethanamine) and;-   Phenisonone    (1-(3,4-Dihydroxyphenyl)-2-[(1-methylethyl)amino]-1-propanone).

Further examples of beta₂ agonists also include those having a structuredifferent from structural formula I:

Un-limited examples are:

-   Tretoquinol (Trimetoquinol,    1,2,3,4-Tetrahydro-1-[(3,4,5-trimethoxyphenyl)methyl]-6,7-isoquinolinediol);    and-   Sibenadet    (4-Hydroxy-7-[2-[[2-[[(3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl]-2(3H)-benzothiazolone).

Additionally, a number of beta₂ agonists are presently known accordingto their Research Code; AR-C68397, CHF-1035, QAB-149 (FromNovartis/Skyepharma), GW-685698 (GSK), GW-159797 (GSK), AD-237 (Arakis,Vectura), HOKU-81, 678007 (GSK), 159802 (GSK), 642444 (GSK), 159797(GSK), 597901 (GSK), KUR-1246, KUL-7211, KUL-1248, AR-C89855, 5-1319 andTA-2005.

Accordingly, a beta₂ agonists of this invention may be selected from thegroup comprising Amiterol; Bamethan; Bitolterol; Butaxamine; Carbuterol;Cimaterol; Colterol; Clenbuterol; Clorprenaline; Colterol; Deterenol;Dioxethedrin; Etafedrine; Ethylnorepinephrine; Fenoterol; Flerobuterol;Formoterol; Hexoprenaline; Indacaterol; Isoetarine;Isoproterenol(Isoprenaline); Mabuterol; Medroxalol; Meluadrine;Nardeterol; Norbudrine; Norepinephrine (Arterenol); Orciprenaline(Metaproterenol); Picumeterol; Pirbuterol; Procaterol; Protokylol;Quinprenaline; Reproterol; Rimiterol; Salbutamol (Albuterol);Salmefamol; Salmeterol; Soterenol; Sulfonterol; Terbutaline;Tulobuterol; Zilpaterol; Zinterol; Broxaterol; Methoxyphenamine;Phenisonone; Tretoquinol (Trimetoquinol); Sibenadet; AR-C68397;CHF-1035; QAB-149; GW-685698 (GSK); GW-159797 (GSK); AD-237 (Arakis;Vektura); HOKU-81; 678007 (GSK); 159802 (GSK); 642444 (GSK); 159797(GSK); 597901 (GSK); KUR-1246; KUL-7211; KUL-1248; AR-C89855; S-1319;TA-2005 or a stereoisomer thereof, an enantiomer thereof, aphysiologically acceptable derivative thereof, and/or a pharmaceuticallyacceptable salt thereof.

In interesting embodiments of the invention, the beta₂ agonist has asuitable log P value and a molecular size that are very well suited andadaptable for topical application to skin. Therefore, a beta₂ agonist ofthis invention preferable has a log P value ranging between −4 to 4,preferable between −3.5 and 3.5, even more preferable between −3 and 3.Optimally, the log P value ranges between −3.5 and 3, such as between−3.5 and 2.5, such as between −3.5 and 2. Furthermore, the molecularweight of a beta₂ agonist of this invention should be less than 800Dalton, preferable less than 700, 600 and 500 Dalton. Even morepreferable less than 450 Dalton, such as less than 400 Dalton. In stillmore preferred embodiments, the molecular weight is less than 300Dalton, such as ranging from about 136 to about 500 Dalton, from about136 to 450 Dalton, 136 to 400 Dalton. In even more preferredembodiments, the beta₂ agonist has a molecular weight ranging from 136to about 350 Dalton, such as from 136 to 300 Dalton.

Therefore, in more preferred embodiments, the beta₂ agonist is acatecholamine derivative selected from the group comprising Amiterol;Bamethan; Butaxamine; Carbuterol; Cimaterol; Colterol; Clenbuterol;Clorprenaline; Colterol; Deterenol; Dioxethedrin; Etafedrine;Ethylnorepinephrine; Isoetarine; Isoproterenol(Isoprenaline); Mabuterol;Medroxalol; Meluadrine; Norbudrine; Norepinephrine (Arterenol);Orciprenaline (Metaproterenol); Procaterol; Rimiterol; Salbutamol(Albuterol); Salmefamol; Salmeterol; Soterenol; Sulfonterol;Terbutaline; Tulobuterol; a stereoisomer thereof, an enantiomer thereof,a physiologically acceptable derivative thereof, and/or apharmaceutically acceptable salt thereof.

In a currently interesting embodiment of the invention, the beta₂agonist is salbutamol or a physiologically acceptable derivativethereof, and/or a pharmaceutically acceptable salt thereof, e.g. thesulphate or hydrochloride salt of salbutamol, or an amino acid salt ofsalbutamol, such as a salt of salbutamol and an amino acid.

As mentioned the beta₂ agonists may be provided as the stereoisomerthereof, the enantiomer thereof, the physiologically acceptablederivative thereof, and/or the pharmaceutically acceptable saltsthereof.

It will be appreciated by those skilled in the art that theabove-mentioned list of beta₂ agonists may be modified at any of thefunctional groups in the compounds to provide physiologically acceptablederivatives thereof. Of particular interest are derivatives formed bymodification of the hydroxyl groups or at the amino groups. It will beappreciated by those skilled in the art that the physiologicallyacceptable derivatives may be derivatized at more than one position.

By the term “physiologically acceptable derivatives thereof” is meantany physiologically acceptable ester, or salt of such ester, of a beta₂agonists of the invention which, upon administration to a human oranimal, is capable of providing (directly or indirectly) a beta₂agonists of the invention or an active metabolite or residue thereof.That is to say that the physiologically acceptable derivative thereof ismeant to define a prodrug of the beta₂ agonist. Typical examples ofsuitable esters are formate, acetate, proprionate, and benzoylate.

By the term “pharmaceutically acceptable salts” is meant salts of abeta₂ agonist that are derived from physiologically acceptable inorganicand organic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic,benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.Furthermore, salts may be derived from natural amino acids, such as froman essential amino acid.

The beta₂ agonist can be supplied in the form of a pharmaceuticallyactive salt, a prodrug, an isomer, a tautomer, a racemic mixture, or inany other chemical form or combination thereof that, under physiologicalconditions, still provides agonistic activity towards thebeta₂-adrenergic receptor. The present invention includes all possiblediastereomers and enantiomers as well as their racemic and resolved,enantiomerically pure forms.

The enantiomeric forms may be of either the (R) or the (S)configuration, or may be a mixture thereof. Thus, the beta₂ agonistaccording to the invention may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures.

The term “stereoisomers thereof” encompasses any isomers that possessidentical constitution, but which differ in the arrangement of theiratoms in space, such as enantiomers, diastereoisomers, and cis-transisomers.

In interesting embodiments of the invention, wherein the beta₂ agonisthas an asymmetric carbon atom, the beta₂ agonist is supplied as anenantiomeric pure or enantiomeric enriched form. The term “enantiomericenriched form” encompasses mixtures of R and S enantiomers, where eitherthe R or the S enantiomer is quantitatively present in excess of eitherthe S or R enantiomer, respectively. When they are diastereoisomers, itis called diastereoselectivity and is quantitatively expressed by thediastereoisomer excess. The enantiomeric enriched form encompassesmixtures of the two enantiomers, where the ratio of the R enantiomer tothe S enantiomer is ranging between 70:30 to 100:0, such as where atleast 70% of the mixture is in the form of the R enantiomer, such as atleast 75%, 80%, 85%, 90; or 95% is present in the form of the Renantiomer.

It is well known in the art that R and S enantiomers often possessdistinctive biological activities. Therefore, in interesting embodimentsof the invention, where the beta₂ agonist is a catecholamine derivativewith one asymmetric carbon atom at C₁ of structural formula I, the beta₂agonist is provided in the R-enantiomeric form because the inventor hasshown that the topical application of this enantiomer does not causeadverse reactions, such as those reported for the corresponding racemicmixture. Furthermore, the inventor has also proved that this enantiomeris effective in the topical treatment of connective tissue diseases.

Therefore, in presently preferred embodiments of the invention, thebeta₂ agonist is provided as the enantiomer, which is pharmacologicallyactive in the treatment of connective tissue diseases and which furtherdoes not cause sensitization of the skin after topical application toskin. According to this invention, such embodiments include at leastenantiomerically pure or enantiomerically enriched R-enantiomer of beta₂agonists comprising in their backbone the spatial R configuration at C₁of structural formula I as depicted above.

Such preferred embodiments of the invention comprises a beta₂ agonistaccording to formula I, wherein the carbon atom C₁ of structural formulaI designate an asymmetric carbon atom with substituents forming anR-configuration.

Thus, a beta₂ agonist of this invention may be provided as theenantiomeric form that has the spatial R-configuration at C₁ ofstructural formula I. Such a beta₂ agonist may be enantiomerically pureor enantiomerically enriched R-enantiomer of a beta₂ agonist selectedfrom Amiterol; Bamethan; Bitolterol; Butaxamine; Carbuterol; Cimaterol;Colterol; Clenbuterol; Clorprenaline; Colterol; Deterenol; Dioxethedrin;Etafedrine; Ethylnorepinephrine; Fenoterol; Indacaterol; Isoproterenol(Isoprenaline); Mabuterol; Meluadrine; Nardeterol; Norbudrine;Norepinephrine (Arterenol); Orciprenaline (Metaproterenol); Picumeterol;Pirbuterol; Quinprenaline; Reproterol; Salbutamol (Albuterol);Salmeterol; Soterenol; Sulfonterol; Terbutaline; Tulobuterol; Zinterol;a physiologically acceptable derivative thereof and/or apharmaceutically acceptable salt thereof. In such embodiments R₃ ofstructural formula I designate hydrido only.

In other embodiments, where R₃ designates a radical selected from thegroup consisting of halogen, C₁₋₆-alkyl, C₄₋₆-cycloalkyl, C₂₋₆-alkenyland C₂₋₆-alkynyl, the beta₂ agonist may be provided in twodiastereomeric forms both having the spatial R-configuration at C₁ suchas the RR or RS diastereomer of Ethylnorepinephrine, Flerobuterol,Formoterol, Hexoprenaline, Isoetarine, Medroxalol,2-(Methylamino)-1-phenyl-1-propanol, Procaterol, Protokylol, Rimiterol,Salmefamol and Zilpaterol a physiologically acceptable derivativethereof and/or a pharmaceutically acceptable salt, wherein the R in RSrefer to the asymmetric carbon C1 of structural formula I. It should beunderstood that such diastereomers can be provided as the diastereomericpure RS or RR isomer or as the diastereomeric enriched RS or RR isomer.

Therefore, the term “R-enantiomers of beta₂ agonist” is meant to includeany beta₂ agonists comprising in their backbone the R-enantiomerconfiguration of structural formula I, despite the fact that they havean additional chiral centre. Thus, an R-enantiomers of a beta₂ agonistencompasses RR and RS enantiomers, where the first mentioned R refer tothe chiral centre of the carbon atom Cl of structural formula I, such asEthylnorepinephrine, Flerobuterol, Formoterol, Hexoprenaline,Isoetarine, Medroxalol, 2-(Methylamino)-1-phenyl-1-propanol, Procaterol,Protokylol, Rimiterol, Salmefamol, Zilpaterol a physiologicallyacceptable derivative thereof and/or a pharmaceutically acceptable salt.

In a current interesting embodiment of the invention the beta₂ agonistis R-salbutamol or a physiologically acceptable derivative thereof,and/or a pharmaceutically acceptable salt thereof, such as the sulphateor hydrochloride salt of R-salbutamol or an amino acid salt ofsalbutamol, such as a salt of salbutamol with an amino acid.R-salbutamol is also known as levo-salbutamol, R-albuterol orlevalbuterol.

Other preferred beta₂ agonists are R-terbutaline and RR-Formoterol.

Manner of Administration and Doses

A beta₂ agonist of the invention may be administered to an individualthrough any route of administration resulting in either local presenceof the agonist in skin or in mucous or systemic presence of the agonist.Routes of administration for the various embodiments include, but arenot limited to, topical, transdermal, nasal, and systemic administration(such as, intravenous, intramuscular, subcutaneous, inhalation, rectal,buccal, vaginal, intraperitoneal, intraarticular, ophthalmic, otic, ororal administration). As used herein, “systemic administration” refersto all nondermal routes of administration, and specifically excludestopical routes of administration.

The phrase “local presence of the agonist in skin or mucous” is meant toinclude topical administration of the beta₂ agonists to skin or mucous,such as mucous of the eye, buccal cavity, nasal cavity, or intestinaltract with the presumption that systemic uptake of the beta₂ agonists islimited or nil. Thus, it is intended that less than 15% by weight, suchas less than 10%, 8%, 5% and 3% by weight, of the topically administeredagonist according to the invention may enter the blood stream or berecovered in urine and feces.

The phrases “systemic presence of the agonist” and “systemicadministration” are interchangeable terms and are meant to include anyform of administration of the beta₂ agonists resulting in the entranceof the agonist into the blood stream. Therefore, the agonist may beadministered by the per-oral, transdermal, transmucosal or theparenteral route.

In a currently interesting embodiment of the invention, the beta₂agonist is intended for the local treatment of the skin and is to beadministered topically, such as to the skin an individual. The treatmentis preferentially accomplished by topical application of a beta₂ agonistas defined herein to the affected skin areas for the local treatment ofthe skin. In such embodiments, the systemic absorption following thetopical application should be limited or nil.

The potency of beta₂-adrenergic agonists varies significantly for whichreason the sufficient clinically relevant dose to be applied as well asthe necessary dosage regimen to be applied may vary significantly.

In the case of systemic administration, the daily total dose wouldtypically be in the range of 0.000001-5 mg/(kg body weight) depending onthe duration of the treatment, the pharmaceutical formulation of thebeta₂ agonist and the bioavailability following per-oral administration,transdermal, transmucosal or parenteral administration. The skilledperson will appreciate that the total daily dose may be divided into oneor more doses, such as two doses per day or three doses per day.

In case of topical administration, the daily dose of thebeta₂-adrenergic agonist is defined according to the concentration ofthe beta₂-adrenergic agonist in the topically administrable composition.The concentration of the beta₂-adrenergic agonist is typically in therange of 0.0001-50.0% (w/w) depending on the duration of the treatment,the type of formulation and the number of times that the topicalcomposition is to be applied daily.

As mentioned in a current interesting embodiment of the invention, thebeta₂ agonist is R-salbutamol or a pharmaceutically acceptable saltthereof and the effective total daily dose with respect to R-salbutamolto be administered systemically is between 0.05 mg to 10 mg, preferablybetween 1-2.5 mg. Concerning, topically administrable R-salbutamol or apharmaceutically acceptable salt thereof, the preferred concentrationwith respect to R-salbutamol is between 0.01-10.0% (w/w), preferablybetween 0.05-5.0% (w/w).

In considering administering a beta₂ agonist, either as the racemicmixture or as the R-enantiomer, topically to skin, a topicallyadministrable composition should preferably comprise the beta₂ agonistin an amount ranging between 0.01 and 10% by weight, preferably between0.05 and 7% by weight, such as between 0.05 and 6% by weight, 0.05 and5.5% by weight, 0.05 and 5% by weight, 0.05 and 4.5% by weight, 0.05 and4% by weight, 0.05 and 3.5% by weight, such as 0.05 and 3% by weight. Instill more preferable embodiments of the invention, the dermatologicalformulation should comprise a beta₂ agonist in an amount ranging between0.2 and 7% by weight, preferably between 0.2 and 6.5% by weight, such asbetween 0.2 and 6% by weight, 0.2 and 5.5% by weight, 0.2 and 5% byweight, 0.2 and 4.5% by weight, 0.2 and 4% by weight, 0.2 and 3.5% byweight, such as 0.2 and 3% by weight. In further preferable embodimentsof the invention, the dermatological formulation should comprise a beta₂agonist in an amount ranging between 0.2 and 2.5% by weight, such asabout 0.5%, 1, 1.5, and 2% by weight.

Topically Administrable Compositions

As mentioned, the safe administration of a beta₂ agonist may require theadministration of an enantiomer or a diastereomer, which does not causesensitization of skin and still possesses beta₂-adrenergic receptoragonistic activity.

Therefore, still another aspect of the invention relates to adermatological/topical administrable pharmaceutical compositioncomprising an R enantiomer of a catecholamine derived beta₂ agonist,either supplied in the form of the enantiomerically pure enantiomer oras the enriched enantiomer; and which composition further comprises oneor more dermatologically acceptable excipients or carriers.

The term “which does not cause sensitization” is meant to define that anenantiomer of a beta₂ agonist does not produce contact sensitization ofskin or ear swelling when applied in a concentration corresponding toits therapeutically effective concentration, typically between 0.5% and5% w/w in the contact sensitization test or ear swelling challenge testdescribed by Kalish R et al (Kalish R et al. Sensitization of mice totopically applied drugs: albuterol, chlorpheniramine, clonidine andnadolol. Contact Dermatitis 1996 August; 35 (2):76-82). Alternatively,test for skin sensitization may be carried out according to theMagnusson and Kligman method (J. Invest. Dermatol. 1969. 52, 268-276)and in accordance with O.E.C.D. Guideline No 406 of Jul. 17, 1992, andthe test method B.6 of the 96/54 E.E.C Directive.

The phrase “topical administrable pharmaceutical composition”encompasses compositions formulated for application to skin and whichare either ready to be applied directly to skin without further dilutionor are the result of diluting a concentrate of the beta₂ agonist in aphysiological acceptable carrier before being applied to skin.

Therefore, the invention provides a topically administrablepharmaceutical composition comprising as the therapeutically activeingredient an enantiomerically pure or an enantiomerically enrichedR-enantiomer of a beta₂ agonist or a physiologically acceptablederivative thereof or a pharmaceutically acceptable salt thereof,wherein the beta₂ agonist is defined according to structural formula II;

wherein the terms Z, Y, X, R₁, R₂, R₃, R′, R″ are as defined above withrespect to structural formula I; and wherein the composition furthercomprises one or more dermatologically acceptable excipient or carrier.

Specifically, such a topically administrable composition comprises asthe therapeutically active ingredient a beta₂-adrenoceptor agonistaccording to formula II or a physiologically acceptable derivativethereof or a pharmaceutically acceptable salt thereof, wherein thecarbon atom at C₁ designate an asymmetric carbon having R-configurationand wherein the terms Z, Y, X, R₁, R₂, R₃, R′, R″ are as defined above.

Such an R-enantiomer (provided as enantiomerically pure or asenantiomerically enriched) is preferably selected from the groupconsisting of enantiomerically pure or enantiomerically enrichedR-enantiomer of Amiterol, Bamethan, Bitolterol, Butaxamine, Carbuterol,Cimaterol, Colterol, Clenbuterol, Clorprenaline, Colterol, Deterenol,Dioxethedrin, Etafedrine, Ethylnorepinephrine, Fenoterol, Indacaterol,Isoproterenol, Mabuterol, Meluadrine, Nardeterol, Norbudrine,Norepinephrine, Orciprenaline, Picumeterol, Pirbuterol, Quinprenaline,Reproterol, Salbutamol, Salmeterol, Soterenol, Sulfonterol, Terbutaline,Tulobuterol, Zinterol, physiologically acceptable derivatives thereof,and pharmaceutically acceptable salts thereof.

Where the beta₂ agonist of structural formula II has more than oneasymmetric carbon, such as two symmetric carbon atoms, the beta₂ agonistmay be provided as the diastereomer where the asymmetric carbon at C₁ ofstructural formula II has the R-configuration. Such beta₂ agonists maybe selected from Flerobuterol, Formoterol, Hexoprenaline, Isoetarine,Medroxalol, Procaterol, Protokylol, Rimiterol, Salmefamol, Zilpaterolphysiologically acceptable derivatives thereof, and pharmaceuticallyacceptable salts thereof.

In still other embodiments, the topically administrable compositioncomprises as the beta₂ agonist the RR or RS diastereomeric form of beta₂agonists selected from Flerobuterol, Formoterol, Hexoprenaline,Isoetarine, Medroxalol, Procaterol, Protokylol, Rimiterol, Salmefamol,Zilpaterol, a physiologically acceptable derivative thereof, and apharmaceutically acceptable salt thereof.

As mentioned, the present inventor has shown that the R-enantiomer ofSalbutamol does not confer skin sensitization to skin following topicalapplication. Therefore, in a currently interesting embodiment of theinvention, the topical composition comprises R-salbutamol or anotherclosely related beta₂ agonist, which also has the R configuration atcarbon atom C₁ of structural formula I.

In a currently interesting embodiment, the topically administrablecomposition comprises:

-   i) R-salbutamol, a physiologically acceptable derivative thereof or    a pharmaceutically acceptable salt thereof; and-   ii) one or more dermatologically acceptable excipients or carriers.

The salt is preferably in the form of the sulphate or hydrochloride saltof R-salbutamol or an amino acid salt of salbutamol, such as a salt ofsalbutamol with an essential amino acid.

The skilled person will appreciate that topically administrablecompositions of the invention may be in any form suitable for beingtopically applied to skin and with the intention to avoid or at leastminimise systemic absorption of the beta₂ agonist.

Accordingly, the composition may be in the form of an emulsion such as acream or a lotion, a gel, a solution, a liniment, an ointment, pasta, aspray, an aerosol, a foam, a liquid or a powder, preferably formulatedin a manner that limits the systemic uptake, e.g. such that less than15% by weight, such as less than 10%, 8%, 5% and 3% by weight, of thetopically administered agonist of the invention enters the blood streamfollowing topical administration to the skin or is recovered in urineand feces.

In other embodiments of the invention, a systemic uptake is tolerable.Therefore, transdermal formulations may also refer to a dermatologicalcomposition of the invention.

The concentration of the beta₂ agonist may vary significantly dependingon its potency. The concentration in the compositions would typically bein the range of 0.0001-50.0 (w/w) depending on the duration of thetreatment, the type of formulation and the number of times that thetopical composition is to be applied daily. More preferable, theconcentration is in the range of 0.01 and 10% by weight, such as moretypically 0.02% and 5%. Even more preferably the concentration isbetween 0.05 and 5% by weight, 0.05 and 4.5% by weight, 0.05 and 4% byweight, 0.05 and 3.5% by weight, such as 0.05 and 3% by weight. In stillmore preferably embodiments of the invention, the dermatologicalformulation should comprise a beta₂ agonist in an amount ranging between0.2 and 7% by weight, preferably between 0.2 and 6.5% by weight, such asbetween 0.2 and 6% by weight, 0.2 and 5.5% by weight, 0.2 and 5% byweight, 0.2 and 4.5% by weight, 0.2 and 4% by weight, 0.2 and 3.5% byweight, such as 0.2 and 3% by weight. In still more preferableembodiments of the invention, the dermatological formulation shouldcomprise a beta₂ agonist in an amount ranging between 0.2 and 2.5% byweight, such as about 0.5%, 1, 1.5, and 2% by weight.

Where the topically administrable composition comprises R-salbutamol ora physiologically acceptable derivative thereof or a pharmaceuticallyacceptable salt thereof, the preferred concentration with respect toR-salbutamol is between 0.01 and 5.0% (w/w), preferably between 0.05 and2.0% (w/w). In view of the good tolerability of R-salbutamol, thecomposition to be administered may contain even higher amounts, such asup to 10 and 20% by weight, e.g. between 0.01% and 10% by weight of thecomposition.

The pharmaceutical compositions of the invention may be formulated inany solid, semi-solid or fluid form suitable for being administeredtopically according to conventional pharmaceutical practice, see, e.g.,“Remington: The science and practice of pharmacy” 20th ed. MackPublishing, Easton Pa., 2000 ISBN 0-912734-04-3 and “Encyclopaedia ofPharmaceutical Technology”, edited by Swarbrick, J. & J. C. Boylan,Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9.

Generally speaking, dermatological compositions may be provided inseveral designs such as in the form of an emulsion (including amicroemulsion and a liposome formulation), gel, solution, liniment,ointment, foam, spray, aerosol, microsponge, patch or powder.

In one embodiment, the topical administrable composition is a cream.Creams are typically oil-in-water emulsions that contain more than 30%of hydrophilic phase, such as water or aqueous buffers.

A typical dermatological formulation for use in the present inventionmay be provided in the form of an emulsion, such as oil-in-wateremulsion consisting of: an R-enantiomer of a beta₂ agonist according tothis invention in an amount ranging between 0.01% and 20% by weight andthe following dermatologically acceptable ingredients: a fatty componentin an amount ranging between 2 and 30% by weight of the composition; anoily component in an amount ranging between 2 and 30% by weight of thecomposition; water in an amount ranging between 30% and 90% by weight ofthe composition; an emulsifier in an amount ranging between 0.2 and 10%by weight of the composition; an emollient in an amount ranging between1 and 20% by weight of the composition; optionally a lipophilic solventin an amount ranging between 1 and 20% by weight of the composition;optionally a hydrophilic solvent in an amount ranging between 1 and 20%by weight of the composition; optionally a thickener in an amountranging between 0.2 and 10% by weight of the composition; optionally aco-emulsifier in an amount ranging between 0.2 and 10% by weight of thecomposition; optionally a preservative in an amount ranging between 0.05and 3% by weight of the composition; optionally an antioxidant in anamount ranging between 0.05 and 3% by weight of the composition;optionally a pH adjuster in an amount ranging between 0.05 and 3% byweight of the composition; optionally a chelating agent in an amountranging between 0.05 and 3% by weight of the composition, with theproviso that all constituents make up 100% by weight of the composition.

According to another embodiment, the composition is formulated as anointment. Ointments are typically water-in-oil emulsions that contain upto 70%, but preferably from approximately 20% to approximately 50%,water or aqueous phases. Hydrocarbons are especially suitable as fattyphase; e.g. vaseline, paraffin oil and/or hard paraffins, whichpreferably contain suitable hydroxy compounds, such as fatty alcohols oresters thereof, for example cetyl alcohol or wool wax alcohol or woolwax, in order to improve their capacity to bind water. Emulsifiers arecorresponding lipophilic substances, such as sorbitan fatty acid esters(Spans), for example sorbitan oleate and/or sorbitan isostearate.Additives to the aqueous phase are, inter alia, moisture-retainingagents, such as polyalcohols, for example glycerol, propylene glycol,sorbitol and/or polyethylene glycol, and preservatives, perfumes, etc.

According to another embodiment, the composition is formulated as anfatty ointment which are anhydrous and contain as base materialespecially hydrocarbons, for example paraffin, vaseline and/or liquidparaffins, and natural or partially synthetic fats, for example coconutfatty acid triglyceride, or preferably hardened oils, for examplehydrogenated groundnut or castor oil, and fatty acid partial esters ofglycerol, for example glycerol mono- or dl-stearate, and also, forexample, the fatty alcohols that increase the water absorption capacityand the emulsifiers and/or additives mentioned in connection with theointments.

According to another embodiment, the composition is formulated as paste,which is a cream and ointment with secretion-absorbing powderconstituents, such as metal oxides, for example titanium oxide or zincoxide, also talc and/or aluminium silicates, the function of which is tobind any moisture or secretions present.

According to another embodiment, the composition is formulated as a gel.In the case of gels, a distinction is made between aqueous and anhydrousor low-water-content gels which consist of swellable, gel-formingmaterials. Especially transparent hydrogels based on inorganic ororganic macromolecules are used. High molecular weight inorganiccomponents having gel-forming properties are predominantlywater-containing silicates, such as aluminium silicates, for examplebentonite, magnesium aluminium silicate, for example veegum, orcolloidal silica, for example aerosil. As high molecular weight organicsubstances, e.g. natural, semi-synthetic or synthetic macromolecules areused. Natural and semi-synthetic polymers are derived from, e.g.polysaccharides having very varied carbohydrate building blocks, such ascelluloses, starches, tragacanth, gum arabic, agar-agar, gelatine,alginic acid and salts thereof, for example sodium alginate, andderivatives thereof, such as lower alkylcelluloses, for example methyl-or ethyl-celluloses, and carboxy- or hydroxy lower alkylcelluloses, forexample carboxymethyl- or hydroxyethyl-celluloses. The building blocksof synthetic, gel-forming macromolecules are, e.g. correspondingsubstituted unsaturated aliphatic compounds, such as vinyl alcohol,vinylpyrrolidine, acrylic acid or methacrylic acid. Examples of suchpolymers are polyvinyl alcohol derivatives, such as polyviol,polyvinylpyrrolidines, such as collidine, polyacrylates andpolymethacrylates, such as Rohagit S or Eudispert. Customary additives,such as preservatives or perfumes, may be added to the gels.

According to another embodiment, the composition is formulated as afoam. Foams are administered, e.g. from pressurised containers and areoil-in-water emulsions in aerosol form, there being used as propellantshalogenated hydrocarbons, such as chlorofluoro-lower alkanes, e.g.dichlorodifluoromethane or dichlorotetrafluoroethane. As oily phase e.g.hydrocarbons, such as paraffin oil, fatty alcohols, for example cetylalcohol, fatty acid esters, such as isopropylmyristate, and/or otherwaxes are used. As emulsifiers, the following mixtures are used: e.g.mixtures of those having predominantly hydrophilic properties, such aspolyoxyethylene sorbitan fatty acid esters (Tweens), and those havingpredominantly lipophilic properties, such as sorbitan fatty acid esters(Spans). The customary additives, such as preservatives, etc. are addedthereto.

Typically, a dermatologically acceptable ingredient to be used in thevarious formulations can be selected from the following ingredients:

-   -   Oily components, which are constituents of the hydrophobic phase        of the various dermatological compositions forms and which may        be made of one of the following dermatologically acceptable        ingredients or a mixture of two or more thereof: almond oil,        castor oil, cacao butter, coconut oil, corn oil, cottonseed oil,        linseed oil, olive oil, palm oil, peanut oil, poppy seed oil,        rapeseed oil, sesame oil, soybean oil, sunflower oil, and        teaseed oil), mineral oils, fatty oils, liquid paraffin, mineral        oil, isopropyl myristate, beewax, cottonseed oil, cetosteraryl        alcohol (including mixtures of cetosteraryl alcohol and sodium        laurilsulfate), lanolin, white soft paraffin, yellow soft        paraffin, canola oil, cetyl alcohol (cetanol), peanut oil, oleic        acid, isopropyl palmitate, castor oil, stearyl alcohol, jojoba        oil, stearic acid and silicone oils.    -   Fatty components, which are constituents of the hydrophobic        phase of the various dermatological compositions forms and may        be used in combination with or instead of the oil phase and        typically includes one or more ingredients selected from        beeswax, paraffin, petrolatum, triglycerides, cetyl palmitate,        vegetable oils, sorbitan esters of fatty acids (Span), solid        macrogols (polyethylene glycols), and condensation products        between sorbitan esters of fatty acids and ethylene oxide, e.g.        polyoxyethylene sorbitan monooleate (Tween). Typical fatty        components may be selected from the group comprising petrolatum,        paraffins, vegetable oils, animal fats, synthetic glycerides,        waxes, lanolin, and liquid polyalkylsiloxanes. Typical fatty        components are but not limited to solid macrogols (polyethylene        glycols).    -   Aqueous phase, which constitutes the hydrophilic phase and which        mainly comprise water, hydrophilic solvents, surfactants,        emulsifier, preservatives, pH adjusters, flavours, colours and        other hydrophilic ingredients.    -   Hydrophilic solvents which may be added to the aqueous phase,        such as polar solvents in the form of water, propylene glycol,        glycerol, sorbitol, ethanol, industrial methylated spirit,        polyethylene glycols, propylene glycols, propylene carbonate,        and triacetin.    -   Lipophilic solvents, such as non polar solvents in the form of        isopropyl alcohol and medium chain triglycerides (MCT) which may        be added to the lipophilic phase.    -   Emollients, such as fatty acid mono, di or tri glycerides, and        fatty acid esters, dodecane, squalane, cholesterol,        isohexadecane, isononyl isononanoate, PPG Ethers, petrolatum,        lanolin, safflower oil, castor oil, coconut oil, cottonseed oil,        palm kernel oil, palm oil, peanut oil, soybean oil, polyol        carboxylic acid esters, derivatives thereof and mixtures        thereof.    -   Emulsifiers (emulsifying agents), which may be added either to        the aqueous phase or to the oil phase: Compositions of the        present invention can include one or more emulsifiers to        emulsify the composition. As used herein, the term “emulsifier”        means an amphiphilic molecule possessing both polar and        non-polar regions which are covalently bound and capable of        reducing the surface tension of water and for the interfacial        tension between water and an immiscible liquid. The term is        meant to include soaps, detergents, emulsifiers, surface active        agents, and the like. The emulsifier can be cationic, anionic,        non-ionic, or amphoteric. This includes a wide variety of        conventional emulsifiers;    -   Non-ionic Emulsifiers. Examples of non-ionic emulsifiers        include, but are not limited to, Polyol esters including glycols        (e.g. ethylene glycol, diethylene glycol, glycol stearate and        propylene glycol monoesters of fatty acids (propylene glycol        stearate, propylene glycol oleate or propylene glycol        palmitostearate)) and glycerol esters (e.g. glyceryl stearate,        glyceryl monooleate, glycerylmonolaurate, glyceryl ricinolate,        glyceryl monocaprylate);    -   Sorbitan derivatives, that consists of esters of cyclic        anhydrides of sorbitol with a fatty acid (C12-C18). Sorbitan        derivatives are divided into two groups i) sorbitan esters of        fatty acids (e.g. sorbitan monolaurate, sorbitan monooleate,        sorbitan monostearate (SPAN 60™), sorbitan monopalmitate,        sorbitan sesquioleate, sorbitan trioleate or sorbitan        tristearate) and ii) polyoxyethylene sorbitan esters (e.g.        polyoxyethylene sorbitan monostearate (TWEEN 60 ™),        polyoxyethylene sorbitan tristearate (TWEEN 65™), polyoxyethlene        sorbitan monooleate (TWEEN 80™);    -   Polyoxyethylene esters (also called macrogol esters) are        mixtures of mono- or di-fatty acids esters (from C12 to C18) of        polyoxyethylene glycol (PEG), e.g. stearate esters of PEG        (PEG-40, PEG-50 and PEG-55), laurate, oleate, and myristate        esters of PEG;    -   Polyoxyethylene ethers are ethers of macrogol and fatty        alcohols, such as ethers of the alcohols: stearyl (steareth        emulsifiers), cetosteraryl (including mixtures of cetosteraryl        alcohol and sodium laurilsulfate, ceteareth emulsifiers) and        oleyl (oleth emulsifiers);    -   Poloxamers that are polyoxyethylene-polyoxypropylene derivatives        with polyoxyethylene groups (e.g. poloxamers-188);    -   Nonylphenyl ethers (nonoxinols) that are ethoxylated        nonylphenols;    -   Propylene glycol Diacetate;    -   Polyvinyl alcohol;    -   Alkanolamides prepared from reaction of fatty acids with mono or        diethanolamine;    -   Fatty alcohols (e.g. cetyl alcohol and stearate alcohol); alkyl        glucosides;    -   alkyl polyglucosides; polyhydroxy fatty acid amides;    -   sucrose esters;    -   fatty acid alkanolamides;    -   ethoxylated fatty acids;    -   ethoxylated aliphatic acids;    -   ethoxylated fatty alcohols (e.g., octyl phenoxy        polyethoxyethanoal available under the trade name TRITON X-100        and nonyl phenoxy poly(ethyleneoxy) ethanol available under the        trade name NONIDET P-40, both from Sigma, St. Louis, Mo.);    -   ethoxylated and/or propoxylated aliphatic alcohols;    -   ethoxylated glycerides;    -   ethoxylated propoxylated block copolymers such as PLURONIC and        TETRONIC surfactants available from BASF.    -   Cationic Emulsifiers. Examples of cationic emulsifiers include,        but are not limited to: salts of primary, secondary, or tertiary        fatty amines that optionally may be polyoxyalkylenated;        quaternary ammonium salts, such as tetraalkylammonium,        alkylamidoalkyltrialkylammonium, trialkylbenzylammonium,        trialkylhydroxyalkylammonium, or alkylpyridinium halides        (preferably chlorides or bromides) as well as other anionic        counter-ions, such as but not limited to, alkyl sulfates, such        as but not limited to, methosulfate and ethosulfate; imidazoline        derivatives; amine oxides of a cationic nature (e.g., at an        acidic pH). Examples of amineoxide emulsifiers include those        which are lauryldimethylamine oxide,        laurylamidopropyldimethylamine oxide, and cetyl amine oxide.    -   Anionic Emulsifiers. Examples of anionic emulsifiers include,        but are not limited to, sarcosinates, glutamates, alkyl        sulfates, sodium or potassium alkyleth sulfates, ammonium        alkyleth sulfates, ammonium laureth-n-sulfates,        laweth-n-sulfates, isethionates, glycerylether sulfonates,        sulfosuccinates, alkylglyceryl ether sulfonates, alkyl        phosphates, aralkyl phosphates, alkylphosphonates, and        aralkylphosphonates. These anionic emulsifiers may have a metal        or organic ammonium counterion.    -   Amphoteric Emulsifiers. Emulsifiers of the amphoteric type        include emulsifiers having tertiary amine groups, which may be        protonated, as well as quaternary amine containing zwitterionic        emulsifiers. Examples of such amphoteric emulsifiers include,        but are not limited to: certain betaines such as cocobetaine and        cocamidopropyl betaine; monoacetates such as sodium        lauroamphoacetate; diacetates such as disodium        lauroamphoacetate; amino- and alkylamino-propionates such as        lauraminopropionic acid. Ammoniurn Sulfonate Amphoterics. This        class of amphoteric emulsifiers refers to “sultaines” or        “sulfobetaines”, such as cocamidopropyl-hydroxysultaine.    -   Preferred emulsifiers are those that have an HLB (i.e.,        hydrophilic to lipophilic balance) of at least 4 and more        preferably at least 6. Even more preferred emulsifiers are        hydrophilic emulsifiers having an HLB in the range between 8 and        20, such as in the range between 10 and 20. Most preferred        emulsifiers have an HLB of at least 12, such as at least 15. One        or more emulsifiers may be used in the compositions of the        present invention at a suitable level to produce the desired        result. In a preferred embodiment, the one or more emulsifier        are present in a total amount of at least 0.1 wt %, more        preferably at least 0.5 wt %, and even more preferably at least        1.0 wt %, based on the total weight of the ready to use        composition. In order to avoid irritation caused by an        emulsifier, in a preferred embodiment the emulsifier is present        in a total amount of no greater than 10 wt %, more preferably no        greater than 5 wt %, even more preferably no greater than 3 wt        %, and even more preferably no greater than 2 wt %, based on the        total weight of the ready to use composition.    -   Polymeric thickeners which may be added to the hydrophilic        phase; e.g. gums such as acacia, alginates, carageenan,        chitosan, collagen, tragacanth and xantham; celluloses, such as        sodium carboxymethyl-, hydroxymethyl-, hydroxypropyl- and        hydroxypropylmethyl celluloses; acrylic acids, such as carbomers        and polycarbophil; colloidal solids such as silica, clays and        microcrystalline cellulose; hydrogels such as polyvinyl alcohol        and polyvinylpyrrolidone; thermoreversible polymers such as        poloxamers.    -   pH adjuster (buffering agents) which may be added to the        hydrophilic phase, such as diethanolamine, lactic acid,        monoethanolamine, triethanolamine, sodium hydroxide, sodium        phosphate, citric acid, acetic acid, tartaric acid, hydrogen        phosphoric acid, phosphate salts and diethylamine.    -   Permeation enhancers, which may be added either to the        hydrophilic or lipophilic phase in order to increase the        penetration of Oxaprozin within stratum corneum.    -   Preservatives, such as antimicrobial agents like        benzalkoniumchloride, benzyl alcohol, chlorhexidine,        imidazolidinyl urea, phenol, potassium sorbate, benzoic acid,        bronopol, chlorocresol, parabens esters, phenoxyethanol and        sorbic acid and mixtures thereof.    -   Humectants may be selected from glycerin, propylene glycol,        sorbitol, lactic acid, urea, and mixtures thereof.    -   Chelating agents, such as citric acid and edetic acid.    -   Antioxidants, such as alfa-tocopherol, ascorbic acid, ascorbyl        palmitate, butylated hydroxyanisole, butylated hydroxytoluene,        cysteinesodium ascorbate, sodium metabisulphite    -   Suspending agents that may be selected from the group comprising        celluloses and cellulose derivatives such as, e.g.,        carboxymethyl cellulose, hydroxyethylcellulose,        hydroxypropylcellulose, hydroxypropylmethylcellulose,        carrageenan, acacia gum, arabic gum, tragacanth, and mixtures        thereof.    -   Gel-forming agents (Thickener). Suitable gel bases and        viscosity-increasing components (thickeners) may be selected        from the group comprising liquid paraffin, polyethylene, fatty        oils, colloidal silica or aluminium, zinc soaps, glycerol,        propylene glycol, tragacanth, carboxyvinyl polymers,        magnesium-aluminium silicates, Carbopol®, hydrophilic polymers        such as, e.g. starch, or cellulose derivatives such as, e.g.,        carboxymethylcellulose, hydroxyethylcellulose and other        cellulose derivatives, water-swellable hydrocolloids,        carrageenans, hyaluronates (e.g. hyaluronate gel optionally        containing sodium chloride), and alginates including propylene        glycol alginate. Further examples are high molecular weight        polysaccharide gum, such as xanthan gum.

Thus, in topically administrable compositions of the invention, thebeta₂ agonist will usually be distributed in a liquid carrier systemsuch as water or any aqueous solution containing organic or inorganicmaterials. Additionally, the compositions may contain one or moreingredients to modify or enhance their texture, appearance, scentperformance or stability. Illustrative additives to the compositionsinclude: oily components, fatty components, ointment bases, hydrophilicsolvents, lipophilic solvents, emollients, water, buffering agents,pH-adjusting agents, preservatives, humectants, chelating agents,antioxidants, stabilizers, emulsifying agents, suspending agents,gel-forming agents, perfumes, skin protective agents, fragrances,antiseptics and preservatives.

Topical administrable compositions of the invention are physically andchemically stable. Where phase-separation of the lipophilic andhydrophilic phase of an emulsion is a problem, it has been foundimportant to select an emulsifier that is less sensitive toelectrolytes. Therefore, in certain preferred embodiments of theinvention, non-ionic emulsifiers shall be selected as the emulsifier.Exemplary non-ionic emulsifiers include, but are not limited to polyolesters including glycols and glycerol esters; sorbitan derivativesincluding sorbitan esters of fatty acids and polyoxyethylene sorbitanesters; polyoxyethylene esters; polyoxyethylene ethers; poloxamers;nonylphenyl ethers. The preferred ones are sorbitan esters of fattyacids and polyoxyethylene sorbitan esters.

The physical stability can be recognised by observing the tendency ofphase separation of the emulsion after challenging the emulsion tophysical stress. For example, the emulsion can be exposed to repeatingcycles of “freeze and thaw”, for example 6 times, followed bycentrifugation. Alternatively, the phase separation can be observedafter prolonged storage of the emulsion at either 25° C., 40° C., or 60°C. for 1 month, 3 months, 6 months, 12 months, optionally aftercentrifugation of the dermatological composition.

In a certain embodiment of the invention, the dermatological compositionis an-oil-in-water emulsion, e.g. provided as a cream or liniment. Theratio between the hydrophilic and lipophilic phase may be adapted in amanner so as to modify the diffusion/solubility of the beta₂ agonistwithin stratum corneum.

The dermatologically administrable pharmaceutical preparations areprepared in a manner known per se by mixing with pharmaceutical adjunctsthat are customary for that purpose, for example by dissolving orsuspending the active ingredient in the base material or in a portionthereof, if necessary. In order to prepare emulsions in which the activeingredient is dissolved in one of the liquid phases, the activeingredient is, as a rule, dissolved therein before the emulsification;in order to prepare suspensions in which the active ingredient issuspended in the emulsion, the active ingredient is mixed with a portionof the base material after the emulsification and then added to theremainder of the formulation.

Further Ingredients

Further ingredients, either therapeutically active ingredients ordermatologically acceptable ingredients can be co-administered togetherwith the beta₂ agonist or added to a medicament or dermatologicalcomposition of the invention in order to strengthen, improve,potentiate, or prolong the therapeutic action demonstrated herein or toprovide a less toxic, safer, more convenient, better tolerated, or lessexpensive treatment approach.

Therefore, in some embodiments of the invention, the medicament,methods, uses and dermatological compositions further comprise one ormore additional therapeutically active ingredient(s). For exampletherapeutically active ingredients generally applied in the treatment ofconnective tissue diseases of the skin, such as NSAID's, andimmunosuppressive agents.

However, in preferred embodiments of the invention, the beta₂ agonistmay be the sole therapeutically active ingredient or the primary/firsttherapeutically active ingredient administered or present in amedicament because of safety concerns. Likewise, dermatologicalcompositions of the invention preferably comprise as the soletherapeutically active ingredient, or as the primary therapeuticallyactive ingredient, a beta₂ agonist as defined herein.

Where it is desirable to add additional therapeutically activeingredients, one or more of the following agents may be excluded from ornot applied in substantial amounts in uses, methods, medicaments anddermatological compositions of the invention, because of safetyconcerns:

-   -   An antihistamine or an analogue thereof, for example those        disclosed in the patent application US2005192261.    -   A corticosteroid, e.g. as disclosed in the patent application        US2005192261.    -   Ibudilast and related compounds as defined by structural formula        I in the patent application WO05051293. (Co-administration with        a corticosteroid or a glucocorticoid receptor modulator)    -   Selective serotonin reuptake inhibitors (SSRI), e.g. as those        disclosed in the patent application US2004220153.    -   Non-steroidal immunophilin-dependent immunosuppressant (NsIDI)        or an NsIDI enhancer (NsIDIE), e.g. as disclosed in the patent        application US2004224876.    -   A steroid, e.g. a steroid as disclosed in the patent application        WO2003092617.

Thus, in one embodiment of the invention, a medicament or a topicallyadministrable composition of the invention does not contain substantialamounts of a steroid, such as a corticosteroid. In still furtherembodiments, the composition does not comprise Ibudilast or a relatedcompound; a selective serotonin reuptake inhibitor (SSRI); anon-steroidal immunophilin-dependent immunosuppressant (NsIDI) and/or anaminosugar.

In another embodiment of the invention, a medicament or a topicallyadministrable composition of the invention does not contain substantialamounts of an anti-histamine; Ibudilast or a related compound; aselective serotonin reuptake inhibitor (SSRI); a non-steroidalimmunophilin-dependent immunosuppressant (NsIDI) and/or an aminosugar.

Likewise, these methods of treating exclude co-administration ofsubstantial amounts of one or more or all of the following drug agents;a steroid; Ibudilast or a related compound; a selective serotoninreuptake inhibitor (SSRI); a non-steroidal immunophilin-dependentimmunosuppressant (NsIDI) and an aminosugar, or exclude theco-administration of an anti-histamine; Ibudilast or a related compound;a selective serotonin reuptake inhibitor (SSRI); a non-steroidalimmunophilin-dependent immunosuppressant (NsIDI) or an aminosugar.

The term “does not contain a substantial amount” is meant to define thatthe amount does not add any contribution to the treatment of aconnective skin disease according to this invention. Typically, suchamounts are less than 5%, such as less than 1% or even more preferableless than 0.1% by weight. In even more preferable embodiments, theamount is nil meaning that the above-mentioned compounds are excludedfrom compositions, methods and uses described herein.

The term “steroid” or “corticosteroid” is meant to define any naturallyoccurring or synthetic compound characterized by a hydrogenatedcyclopentanoperhydrophenanthrene ring system. Naturally occurringcorticosteroids are generally produced by the adrenal cortex. Syntheticcorticosteroids may be halogenated. Examples of corticosteroids areprednisolone, cortisone, dexamethasone, hydrocortisone,methylprednisolone, fluticasone, prednisone, triamcinolone, andDiflorasone.

The term “Ibudilast or a related compound” is meant to define Ibudilastor a derivative of a pyrazolopyridine as defined in the patentapplication WO 2005/051293:

The term “selective serotonin reuptake inhibitor (SSRI)” is meant todefine any member of the class of compounds that (i) inhibit the uptakeof serotonin by neurons of the central nervous system, (ii) have aninhibition constant (Ki) of 10 nM or less, and (iii) a selectivity forserotonin over norepinephrine (i.e., the ratio of Ki(norepinephrine)over Ki(serotonin)) of greater than 100. Typically, SSRIs areadministered in dosages of greater than 10 mg per day when used asantidepressants. Examples of SSRIs for use in the invention arefluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, andvenlafaxine.

The term “non-steroidal immunophilin-dependent immunosuppressant or(NsIDI)” includes any non-steroidal agent that decreases proinflammatorycytokine production or secretion, binds an immunophilin, or causes adown regulation of the proinflammatory reaction. NsIDIs includecalcineurin inhibitors, such as cyclosporine, tacrolimus, ascomycln,pimecrolimus, as well as other agents (peptides, peptide fragments,chemically modified peptides, or peptide mimetics) that inhibit thephosphatase activity of calcineurin. NsIDIs also include rapamycin(sirolimus) and everolimus, which binds to an FK506-binding protein,FKBP-12, and block antigen-induced proliferation of white blood cellsand cytokine secretion.

The term “anti-histamine” defines a compound that blocks the action ofhistamine. Classes of antihistamines include, but are not limited to,ethanolamines, ethylenediamine, phenothiazine, alkylamines, piperazines,and piperidines. Examples of Anti-histamines are bromodiphenhydramine,clemizole, cyproheptadine, desloratadine, loratadine, thiethylperazinemaleate, and promethazine.

Furthermore, one or more of the following agents may be excluded fromco-administration with the beta₂ agonist or to be included in amedicament or a dermatological composition of the invention:

-   -   1,3-bis-(substituted-phenyl)-2-propen-1-ones as disclosed in the        patent application US2003236298, e.g.        1,3-bis-(substituted-phenyl)-2-propen-1-ones that has at least        one phenyl substituent that is an aryl, heteroaryl or        heterocyclic moiety.    -   An aminosugar as disclosed in the patent applications        US2005130935 or WO 2003097073, such as an aminosugar selected        from the group consisting of glucosamine, galactosamine,        mannosamine, derivatives and salts thereof, e.g. wherein the        aminosugar is N-acetylglucosamine, N-acetylgalactosamine or        N-acetylmannosamine is excluded from uses, methods and        compositions of the invention.    -   pyridazine derivatives as described in US20050176714 or        WO2003104204

The term “1,3-bis-(substituted-phenyl)-2-propen-1-ones” refers to thosecompounds defined by the general formula (1) in the patent applicationUS2003236298, e.g. 1,3-bis-(substituted-phenyl)-2-propen-1-ones that hasat least one phenyl substituent that is an aryl, a heteroaryl or sheterocyclic moiety.

The term an “aminosugar” is meant to include those defined in the patentapplications, US2005130935 and WO2003097073, such as to encompass one ormore amino derivatives of a monosaccharide (aldoses and ketoses) and itscorresponding sugar alcohols (alditols) such as trioses, tetroses,pentoses, hexoses, heptoses and octoses. The aldose, ketose, or alditolhas one or more hydroxy groups replaced by any amino group at anyposition, including the anomeric position. An aminosugar is thus adeoxyamino derivative of an aldose, ketose, or alditol. The term is alsointended to mean polyamino sugars, wherein more than one hydroxy grouphas been replaced by an amino group (e.g. dideoxydiamino,trideoxytriamino-derivatives). Moreover, the term “aminosugar” is alsointended to mean amino derivatives of di-, oligo- and poly-saccharidescomprising at least one of said monosaccharides. Consequently, in thecase of dl-, oligo- and poly-saccharides, the amino group may be theposition of glycosidation.

The term “pyridazine derivative” is meant to include those compoundsdescribed by the formula (1) in US20050176714 or WO2003104204. Suchpyridazine derivatives are phosphodiesterase IV inhibitors.

Furthermore, one or more of the following agents are undesirable indermatological compositions: a skin irritant, a cannabinoid orcannabinoid receptor agonist (as disclosed and defined in the patentapplication WO05102296), an antigen (as disclosed and defined inWO03088997), a scrubbing agent (such as those defined in the patentapplication JP7304647), a compound of the plant of pepper family (e.g.Piper nigrum L, Piper longum L, Piper angustifolium), (such as compoundsdefined and disclosed in the patent application JP9110674), adissolution assistant agent (such as those defined and disclosed in JP61-154201), an inorganic salt or an organic acid (such as thosedisclosed and defined in the patent application JP 06-048497), ahypoglycemic agent (such as those disclosed and defined in the U.S. Pat.No. 4,088,756.

EXAMPLES Example 1

Topically Administrable Composition of a Beta-₂ Adrenoceptor Agonist.

A pharmaceutical composition according to the invention was prepared bydissolving R-salbutamol sulphate in the watery phase prior to mixing theoily phase and watery phase of the following composition (w/w):

Hydrophobic Phase:

Petrolatum 5.0% Paraffin oil 10.0% Cetylan (mixture of 9 parts ofcetosteraryl alcohol 5.0% and 1 part of sodium laurilsulfate) Glycerylmonosterate 6.0% Polyoxyethylene sorbitan monooleate (Tween 80) 0.5%Hydrophilic Phase:

R-Salbutamol sulphate 0.5% Propylene glycol 5.0% Benzylalcohol 0.5%Water: Ad 100%

The emulsion was prepared by first dissolving R-salbutamol sulphate inthe watery phase, heating the two phases to 70° C. and then mixing thetwo phases and finally cooling the mixture under agitation.

Examples 2 to 5 concern the treatment of cutaneous manifestation inpatients suffering from discoid Lupus Erythematosus or subacute LupusErythematosus with the topical composition of Example 1 under thecontrol of a medical doctor of Bispebjerg Hospital, Denmark. Thecomposition was applied to affected areas once or twice per day.

Example 2

A 50 year old woman had been suffering from discoid Lupus Erythematosusfor 18 years. Her arms were somewhat affected and the fingers wereseverely affected with acrocyanosis. During the years, the woman hadregularly been treated with strong topical steroids, but with limitedeffect.

During an aggravation of the disease, which especially affected thefingers, the woman initiated a treatment with the emulsion according toexample 1 on the fingers. After 6 weeks of treatment the subjectexperienced an almost complete recovery and the symptoms of discoidLupus Erythematosus had virtually gone. The treatment was continued foranother 3 months maintaining the fingers free of symptoms.

Example 3

A 59 year old woman had been suffering from discoid Lupus Erythematosusfor 6 years. The symptoms started on the chin, but had spread to most ofthe face.

The woman had periodically been treated with strong topicalcorticosteroids, topical tacrolimus and systemic methotrexate, butwithout significant improvement of the disease. During an aggravation ofthe symptoms, the subject initiated a twice daily treatment with theemulsion according to example 1. After 4 weeks of treatment, there was asignificant reduction in facial erythema. Newer, smaller patches oferythema disappeared completely after 1 to 2 weeks of treatment.

Example 4

A 66 year old woman had been suffering from discoid Lupus Erythematosusfor 32 years. The disease was very severe with a strong affection of thearms and the back and with elements spread to other parts of the body.The woman had been treated with ercoquin and strong topicalcorticosteroids, but with limited effect.

During an aggravation of the symptoms, the woman initiated a twice dailytreatment with the emulsion of example 1. During the first 6 weeks oftreatment the subject experienced a significant improvement of largerelements, while small, new elements disappeared completely within daysof treatment.

Example 5

An 81 year old woman had been suffering from subacute LupusErythematosus for 16 years. The subject was affected on large areas ofthe body with elements on the back, the breast and the face.

The woman has previously been treated with oral prednisolone,chlorochin, thalidomide and strong topical steroids, but all withlimited or no effect.

During an aggravation of the symptoms, the woman initiated a twice dailytreatment with the emulsion according to example 1. After 3 weeks oftreatment, a significant reduction of all elements was observed. After 7weeks of treatment, the back was completely free of elements.

Example 6

Assessment of sensitising properties of R-salbutamol. Test for skinsensitization is carried out according to the Magnusson and Kligmanmethod (J. Invest. Dermatol. 1969. 52, 268-276) and in accordance withO.E.C.D. Guideline No 406 of Jul. 17, 1992, and the test method B.6 ofthe 96/54 E.E.C Directive.

Procedure:

The test item (R-salbutamol as the sulphate salt) was diluted withdistilled water to prepare a concentration of 0.5% (w/v).

Albino guinea pigs of Dunkin-Hartley strain were exposed to the testitem after an acclimatisation period of at least five days.

The Maximum Non Necrotizing Concentration (M.N.N.C.) was determined byinjecting by intradermal route the following concentrations of the testitem 0.25%, 0.125%, 0.0625%, 0.0312% and 0.0156% diluted inphysiological saline solution.

Pre-Maximum Non Irritant Concentration (pre-M.N.I.C.) was determined byapplication of the test item under an occlusive dressing during 24hours, at the following concentrations: 0.5%, 0.25%, 0.125% and 0.0625%diluted in physiological saline solution.

Maximum Non Irritant Concentration (M.N.I.C.) was determined byinitially establishing an induction phase by intradermal injection witha physiological saline solution and by topical application of distilledwater followed by a 18-day rest phase. In the challenge phase where thetest item is under occlusive dressing for 24 hours, the test item wasapplied to the skin of the Albino guinea pigs at the followingconcentrations: 0.5%, 0.25%, 0.125% and 0.0625% diluted in physiologicalsaline solution. The induction phase was performed by intradermalinjection at day 0 the test item at a concentration of 0.5% and bytopical application at day 7 of the test item at 0.5% after brushingwith a solution of sodium lauryl sulfate.

Results:

No macroscopic cutaneous reactions attributable to allergy was recordedduring the examination following the removal of the occlusive dressing(challenge phase) from the treated test animals. No cutaneousintolerance reaction was recorded in animals from the negative controlgroup.

Example 7

The efficacy and safety of a beta₂ agonist in the treatment of patientswith cutaneous LE can be determined according to a placebo controlledand double blind proof of concept study.

Patients (at least 30 divided in two groups) with clinical diagnosis ofeither SLE or DLE presenting with a newly developed discoid lesion inthe skin are to be enrolled in the study. Only fresh inflammatorylesions will be examined in the study. Investigators will select onelesion (target lesion) on each patient and examine this particularlesion at each visit. The treated area must not exceed 100 cm².

There will be two treatment groups: Half of the patients enrolled in thestudy will treat the selected lesional area with the cream 0.5% ofexample 1 and half of the patients will treat the selected lesional areawith placebo cream. Treatments will be performed twice daily for 8weeks. Investigator will assess signs and symptoms (Erythema,Scale/Hypertrophy, Dyspigmentation, Scarring/Atrophy/Panniculitis andInduration), measure lesion area and the patient will assess itching andpain (confined to the target lesion) on a visual analogue scale atbaseline and after 2, 4, 6 and 8 weeks of treatment.

General improvement (scored by investigator) and patient's assessment ofglobal improvement of the treated lesion will be assessed after 2, 4, 6and 8 weeks of treatment.

The investigator's assessment of erythema will be performed according tothe following score: 0=absent, 1=pink; faint erythema, 2=red, 3=darkred; purple/violaceous/crusted/hemorrhagic.

The investigator's assessment of scale/hypertrophy will be performedaccording to the following score: 0=absent, 1=scale,2=verrucous/hypertrophic.

The investigator's assessment of dyspigmentation will be performedaccording to the following score: 0=absent, 1=dyspigmentation.

The investigator's assessment of scarring/atrophy/panniculitis will beperformed according to the following score: 0=absent, 1=scarring,2=severely atrophic scarring or panniculitis.

The investigator's assessment of induration will be performed accordingto the following score: 0=absent, 1=induration, 2=severe induration.

The investigator's assessment of general improvement of the targetlesion will be performed according to the following score: −1=worsened,0=no change, 1=mild improvement, 2=moderate improvement, 3=completelyhealed.

The patients will be asked to assess the global improvement of thetarget lesion according to the following score: −1=worsened, 0=nochange, 1=mild improvement, 2=moderate improvement, 3=completely healed

Patients will assess pain and itching in the target lesion using avisual analog scale from 0 to 10.

The invention claimed is:
 1. A method of treating dermatomyositis,comprising topically administering to the skin of an individual withdermatomyositis a composition comprising R-salbutamol, a physiologicallyacceptable derivative thereof, or a pharmaceutically acceptable saltthereof, wherein the composition comprises R-salbutamol in an amountranging between 0.2 and 2.5% by weight, and wherein the R-salbutamol isthe sole therapeutically active agent in the composition.
 2. The methodof claim 1, wherein the composition is topically administered once perday.
 3. The method of claim 1, wherein the composition is topicallyadministered twice per day.